1. Field of the Invention
The present invention relates to a drug delivery system for a combination of medicaments for use in inhalators for the treatment of respiratory, systemic and topical diseases, for gene therapy, for vaccine administration, and for administration of antigens and adjuvants (i.e. birth control). More particularly, the present invention relates to a drug delivery system for the use of a combination of therapeutic agents for the treatment of respiratory diseases, e.g., asthma of whatever type or genesis, including intrinsic (non-allergic) and extrinsic (allergic) chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), emphysema, bronchitis, acute lung injury (ALI), pneumoconiosis, acute respiratory distress syndrome (ARDS), cystic fibrosis (CF), allergic rhinitis and exacerbations of airways hyperactivity consequent to other drug therapy. Other combinations of medicaments for use in inhalators may be used to treat systemic or topical disorders including lung and other cancers, infectious diseases including influenza, diabetes, immuno-compromised diseases including acquired immune deficiency syndrome (AIDS), bone degenerative diseases including osteoporosis, neurological degenerative diseases, including Alzheimer's and Parkinson's disease, pain management, cardiovascular disease, obesity, hepatitis, dermatological diseases, arthritis, hypertension and neurological disorders including depression.
3. State of the Art
The majority of commercially available inhalators are used in the treatment of respiratory disorders, e.g., asthma. Asthma is a chronic disease that affects millions of people in the United States, and a much larger number around the world. Asthma is typically initiated by the inhalation of antigens (sensitive patients) but, in some patients, there is a poorly defined mechanism(s) resulting in asthma and which is not associated with an antigen. Asthma is a condition characterized by inflammation and bronchial airway constriction that obstructs the patient's ability to breathe, resulting in wheezing, coughing and tightness of the chest.
There are many different medications used for treating asthma. While some patients respond sufficiently well to one type of medication or another, it is common for moderate to severe asthmatics to use more than one medication. Typically, a corticosteroid, e.g., beclomethasone or its derivatives and solvates, is used to minimize asthma symptoms by decreasing the airway hyper-responsiveness and inflammation while a bronchodilator, e.g., albuterol or its salt, is used to increase lung function and reduce the incidence of bronchial constriction. However, due to the short-acting relief provided by the bronchodilator, i.e., the bronchodilator must be administered frequently, e.g., 4-6 times per day, which may result in poor patient compliance. Furthermore, the bronchodilator product is less suitable for nocturnal asthma since it may not be effective through the duration of normal sleep.
Traditionally, the bronchodilator and steroidal product have been provided in separate medicament inhalators. For example, an inhalator may be used for the corticosteroid, while a separate inhalator is used for the bronchodilator. The use of two inhalers, however, has been found to be disadvantageous. Specifically, a patient using two inhalators increases the likelihood that the patient will fail to comply with the treatment protocol or may forget to take one of the medications.
Recently, more potent and/or longer-acting corticosteroids, e.g., fluticasone propionate, and beta2-agonist bronchodilator drugs, e.g., salmeterol and or its salt, have been developed. This has led to improved patient compliance, which can reduce emergency room visits and reduce the risks associated with nocturnal asthma.
In 1993, Glaxo Group Ltd. was issued U.S. Pat. No. 5,270,305 for a pharmaceutical composition comprising salmeterol (a long-acting beta2-agonist) and fluticasone propionate (steroid) as a combined preparation for the treatment of respiratory disorders, including the simultaneous, sequential or separate administration by inhalation via either a metered dose inhaler (MDI) or dry powder inhaler (DPI). This combination therapy had markedly greater efficiency and duration of bronchodilator action than previously known combinations. In addition, it permitted the establishment of a twice-daily dosing regimen with consequent substantial benefits in, for example, the treatment of asthma, particularly nocturnal asthma.
In 1997, Astra Aktiebolag was issued U.S. Pat. No. 5,674,860 for a combination product consisting of formoterol (long-acting beta2-agonist) and budesonide (steroid) for the treatment of mild as well as severe asthma and other respiratory disorders, including delivery via an MDI, DPI or nebulization. Additional patents covering combination products for the treatment of respiratory disease include U.S. Pat. Nos. 5,972,919, 6,030,604, and 6,183,782.
Recently, these combinations of the steroid and bronchodilator drugs have been commercialized in dry powder inhalers, i.e., ADVAIR® medicament in the DISKUS® dry powder inhalator, and SYMBICORT® medicament in the TURBUHALER® dry powder inhalator. It has been found that the use of the two medicaments together improved patient treatment. Additionally, requiring a patient to use a single inhalator increases the likelihood of patient compliance as the patient need only remember a more limited number of medicament applications.
It is evident from the above discussion that there is often a synergistic effect of a combination of drugs when the two drugs are administered together. It is likewise evident from the above discussion that the use of a single inhalator increases the likelihood of patient compliance as the patient need only remember a more limited number of medicament applications.
While combining medications is advantageous in some ways, it also raises concerns. Many medicaments are disposed on a carrier, such as lactose. While the carrier can be carefully selected to a particular medicament, the presence of multiple medicaments or multiple carriers may render the medicaments and/or carriers unstable. This, in turn, places limitations on the combinations of medicaments which can be used together. By eliminating the interaction of medicaments during storage, however, a broad range of medicaments can be administered substantially simultaneously.
It is therefore an object of the present invention to address the delivery of a combination of medicaments for the treatment of respiratory, systemic and topical diseases from dry powder inhalators (DPIs), such as the DPI device in U.S. Pat. No. 6,209,538 and other devices.